Studies of the microsomal electron transport system responsible for the oxidative metabolism of many drugs has revealed the complexity of the pattern of regulation resulting from the stoichiometry of the requisite electron carrier enzymes and the limitations imposed by association of these enzymes with a membrane. Measurements of the kinetics of cytochrome P-450 reduction under a variety of conditions point to the role of membrane fluidity and alterations in the rate limiting step of the reaction sequence as major factors dictating the rate of drug metabolism. Associated studies of drug interaction with cytochrome P-450, hydrogen peroxide generation as an indicator of active oxygen, product adduct formation, and evaluation of endogenous substrate effects all characterize the potential multiple sites of control of this enzyme system. Comparative studies have been carried out using enzymes from liver, kidney, lung, and adrenal cortex. The specific aims of this research program are to further our understanding of the molecular events associated with cytochrome P-450 function during drug metabolism in vitro and in vivo.